**Acknowledgements**

Research Alliance under the MRCG-HRB Joint Funding Scheme, grant number HRB-MRCG-2016-2.

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

women living with T2DM.

and take longer to heal [111, 118].

and economically [178].

and mortality of T2DM globally [181, 182].

vastly different for women post-menopause) to average height, life span and access to appropriate treatment. Many of these biological traits, and also psychosocial and socioeconomic traits that impact risk vary widely geographically. Understanding the epidemiology and physiological mechanisms of DM-associated complications, including the role of gender, allows for the implementation of appropriate treatment

In the non-DM population, oestrogens such as estradiol are protective against some of these comorbidities but the protective effects are often diminished in a DM context. This pattern is evident in both CVD and CKD where women with DM undergo a much larger relative increase in risk compared to men. Numerous studies have also shown that women are less often prescribed ACE inhibitors and lipid lowering drugs, including statins [56–60]. This prescription bias compounds the higher rates of CVD and CKD in women with T2DM, leading to increased mortality rates, a major factor in the high T2DM-assocaited mortality in women [30]. Therefore, particular awareness needs to be paid to the gender discrepancy in patient care in the context of T2DM in order to address this inequality and improve outcomes for

The onset of diabetic retinopathy is also linked to sex hormones - with levels of androgens correlating to likelihood of diagnosis. There is therefore increased incidence of diabetic retinopathy in men compared to women. Contrasting to this, neuropathy incidence, though higher in men, does not correlate directly with gender but instead with height which is a predictor of neuropathy development in both diabetic and non-diabetic populations [111, 118]. Therefore the higher rates in men in many regions are likely due to the greater average height of men with the causality possibly being longer nerve fibres which are more susceptible to injury

Diabetic osteopathy is one of the less-reported complications of DM. People living with T2DM experience higher fracture rates both due to increased rates of falling and due to poorer bone health, which is present despite increased BMD [159]. In terms of the role of gender in diabetic osteopathy, the disorder follows an opposite pattern to that seen in CVD and DKD. Poor bone health experienced primarily by women in the non-DM population as they age is largely absent in men, but in the context of DM there is an increased relative risk for men to experience, for example, hip fracture [149, 156]. Fractures such as these are associated with high morbidity, especially functional limitations that results in loss of independence – physically

Interestingly, the overall mortality rates and cost of treatment associated with DM are higher in women than in men despite the general preponderance of comorbidity in men. A number of factors may explain this discrepancy. Firstly, women with DM are older, and epidemiologically there is increased cost of treatment and higher mortality with age. Secondly, regions with high DM-associated mortality (low- and middle-income countries) also report higher rates of DM in women [1]. Finally, men are reported to develop DM with a reduced risk-factor burden (eg. lower BMI). Though this indicates a greater risk of DM development for men, it also signifies that women, once they do develop DM, are diagnosed with such along with a greater set of risk factors for DM complications. These risk factors include inadequate blood glucose control, high blood pressure, high BMI and reportedly less frequent exercise [179]. Though not all women will experience pregnancy, for those that do, their glycaemic control during this time is a strong predictor of future development of T2DM [180]. Targeting those women who experience gestational diabetes for education or treatment options for T2DM would be an effective way of reducing diabetic burden in women and therefore reducing associated morbidity

and research programmes that ultimately reduce morbidity and mortality.

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